UNASSIGNED: Mandibular reconstruction has historically been challenging due to the complex, highly functional, and esthetic nature of the anatomy. The most common etiologies of these defects requiring resection include trauma, benign tumors, and malignant pathology. Mandibular defects have been treated with little consideration for neural reconstruction, leaving patient\'s orally incompetent with associated social stigma. Although recent advances in reconstructive techniques improve oral rehabilitation, immediate inferior alveolar nerve (IAN) reconstruction has not been widely adapted.
UNASSIGNED: Here-in we seek to discuss the innovations of neural reconstruction of large segment mandibular defects and associated IAN defects and present an example case performed at Naval Medical Center San Diego (NMCSD).
UNASSIGNED: Pertinent literature discussing maxillofacial reconstruction and nerve repair using autogenous nerve harvest and allograft was queried from available online resources.
UNASSIGNED: Six patients have received immediate reconstruction of the IAN using processed nerve allograft over the past three years. All obtained sensation to S3 within six months of surgery.
UNASSIGNED: IAN repair using nerve allografts in conjunction with free flap reconstruction for large mandibular defects is a viable treatment and should be the new paradigm in maxillofacial reconstruction as it provides substantial quantifiable and qualitative improvements in social, functional, and esthetic outcomes of care.

Peripheral nerve injuries are prevalent and their treatments present significant challenges. Among the various reconstructive options, nerve conduits and wraps are popular choices. Advances in bioengineering and regenerative medicine have led to the development of new biocompatible materials and implant designs that offer the potential for enhanced neural recovery. Cost, nerve injury type, and implant size must be considered when deciding on the ideal reconstructive option.

Aim: Peripheral nerve injury (PNI) is a debilitating condition with significant associated morbidity, and which places a substantial socioeconomic burden on healthcare systems worldwide. Recently, allograft has emerged as a viable surgical alternative to autograft for the treatment of PNI. This study evaluated the cost effectiveness of allograft (Avance® Nerve Graft) compared with autograft for the peripheral nerve repair, from a US payer perspective. Methods: A Markov cohort model was developed to consider the treatment pathways followed by a patient population undergoing a single transected nerve repair with either allograft, or autograft. The marginal difference in meaningful recovery (MR) (effectiveness), and costs, between the two groups were estimated over a lifetime horizon. Deterministic and probabilistic sensitivity analyses (PSA) were performed to consider the uncertainty surrounding the base-case input parameter values and their effect on the overall incremental cost-effectiveness ratio (ICER). Results: The base-case analysis indicates that there is a small difference in the average probability of MR between the two groups (75.15% vs 70.46%; +4.69% with allograft). Allograft also results in cost savings ($12,677 vs $14,023; -$-1346 with allograft) compared with autograft. Deterministic sensitivity analysis shows that the costs of the initial surgical procedures are the main drivers of incremental cost, but that the intervention is likely to be cost saving compared with autograft regardless of the parameter variations made. Conclusion: The use of allograft with the Avance Nerve Graft has the potential to be a cost-effective alternative to autograft for the surgical treatment of PNI in the USA.

The loss of function resulting from peripheral nerve injuries confers a significant burden to the patient and society. The treatment of peripheral nerve injuries requires an accurate diagnosis and formulation of a functional reconstructive plan. Advances in peripheral nerve imaging complement electrodiagnostic studies, and provide us with detailed information regarding the status of nerve injury, repair, and regeneration in order to prognosticate recovery and determine the need for surgical intervention. When direct nerve repair is not possible, the methods for bridging a nerve gap are the nerve autograft, allograft and conduit. While current research supports the use of conduits and nerve allografts for shorter nerve gaps, the nerve autograft still remains the gold standard for bridging a nerve gap. When direct nerve repair or nerve grafting fails, or is anticipated to be insufficient, nerve transfers are an alternative for reconstruction. Knowledge of axonal counts, upper limb innervation patterns, location and clustering of upper limb peripheral nerves allows for the design of new nerve transfers. The options of nerve transfers for radial, ulnar and median nerve injuries are outlined, as well as their outcomes. Nerve transfers are an attractive option for restoring motor and sensory function while minimizing donor site morbidity. However, one must consider their limitations, and preserve donor sites for secondary tendon transfer options. This article presents the latest information regarding the imaging of peripheral nerves, methods to bridge a nerve gap, and nerve transfers to aid the peripheral nerve surgeon in choosing a reconstructive plan.

Neurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.

Peripheral neurological complications are seen after SARS-CoV-2 infections. These are mostly immune-mediated such as Guillaine-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. We present a 39-year-old man treated with a right sciatic nerve allotransplantation with subsequent clinical and electrophysiological improvement within 30 months of observation. After SARS-CoV-2 infection, he developed clinical deterioration with selective sciatic nerve demyelination in a nerve conduction study. Nerve conduction velocity returned to previous values within six months of treatment. Intravenous immunoglobulins were used at standard dosage. The inflammatory immune process seemed to be a cause of peripheral demyelination isolated to a nerve allograft with good reaction for intravenous immunoglobulin treatment.

Acellularized nerve allografts (ANAs) have been developed as substitutes for nerve autograft to promote nerve regeneration after surgical repair. In this video, the authors demonstrate operative techniques for using ANAs to repair potentially functional nerve fascicles during tumor resection. A 67-year-old female with schwannomatosis requested resection of a painful enlarging mass of the left ulnar nerve proximal to the elbow. During surgery, neuromonitoring suggested that fascicles entering the tumor could be functional. Therefore, nerve allograft was used to repair the transected fascicles. The patient recovered with full strength and sensation in the ulnar distribution, with resolution of her preoperative symptoms. The video can be found here: https://stream.cadmore.media/r10.3171/2022.10.FOCVID22101.

Segmental peripheral nerve injuries (PNI) are the most common cause of enduring nervous system dysfunction. The peripheral nervous system (PNS) has an extensive and highly branching organization. While much is known about the factors that affect regeneration through sharp bisections and linear ablations of peripheral nerves, very little has been investigated or documented about PNIs that ablate branch points. Such injuries present additional complexity compared to linear segmental defects. This study compared outcomes following ablation of a branch point with branched grafts, specifically examining how graft source and orientation of the branched graft contributed to regeneration. The model system was Lewis rats that underwent a 2.5 cm ablation that started in the sciatic nerve trunk and included the peroneal/tibial branch point. Rats received grafts that were rat sciatic autograft, inbred sciatic allograft, and inbred femoral allograft, each of which was a branched graft of 2.5 cm. Allografts were obtained from Lewis rats, which is an inbred strain. Both branches of the sciatic grafts were mixed motor and sensory while the femoral grafts were smaller in diameter than sciatic grafts and one branch of the femoral graft is sensory and the other motor. All branched grafts were sutured into the defect in two orientations dictated by which branch in the graft was sutured to the tibial vs peroneal stumps in recipients. Outcome measures include compound muscle action potentials (CMAPs) and CatWalk gait analysis throughout the recovery period, with toluidine blue for intrinsic nerve morphometry and retrograde labeling conducted at the 36-week experimental end point. Results indicate that graft source and orientation does play a significant role earlier in the regenerative process but by 36 weeks all groups showed very similar indications of regeneration across multiple outcomes.

Decellularized nerve allografts are an alternative to autograft for repairing severe nerve injuries, since they have higher availability and do not induce rejection. In this study, we have assessed the regenerative potential of a novel decellularization protocol for human and rat nerves for repairing nerve resections, compared to the gold standard autograft. A 15-mm gap in the sciatic nerve was repaired with decellularized rat allograft (DC-RA), decellularized human xenograft (DC-HX), or fresh autograft (AG). Electrophysiology tests were performed monthly to evaluate muscle reinnervation, whereas histological and immunohistochemical analyses of the grafts were evaluated at 4 months. A short-term study was also performed to compare the differences between the two decellularized grafts (DC-RA and DC-HX) in early phases of regeneration. The decellularization process eliminated cellularity while preserving the ECM and endoneurial tubules of both rat and human nerves. Higher amount of reinnervation was observed in the AG group compared to the DC-RA group, while only half of the animals of the DC-HX showed distal muscle reinnervation. The number of regenerating myelinated axons in the mid-graft was similar between AG and DC-RA and lower in DC-HX graft, but significantly lower in both DC grafts distally. At short term, fibroblasts repopulated the DC-RA graft, supporting regenerated axons, whereas an important fibrotic reaction was observed around DC-HX grafts. In conclusion, the decellularized allograft sustained regeneration through a long gap in the rat although at a slower rate compared to the ideal autograft, whereas regeneration was limited or even failed when using a decellularized xenograft.

Neurofibromatosis Type 2 (NF2) is a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2. Patients develop vestibular schwannomas (VS), peripheral schwannomas, meningiomas, and ependymomas. There are no approved drug therapies for NF2. Previous work identified phosphoinositide-3 kinase (PI3K) as a druggable target. Here we screened PI3K pathway inhibitors for efficacy in reducing viability of human schwannoma cells. The lead compound, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, was further evaluated for its effects on isolated and nerve-grafted schwannoma model cells, and primary VS cells. CUDC907 (3 nM IG50) reduced human merlin deficient Schwann cell (MD-SC) viability and was 5-100 fold selective for MD over WT-SCs. CUDC907 (10 nM) promoted cell cycle arrest and caspase-3/7 activation within 24 h in human MD-SCs. Western blots confirmed a dose-dependent increase in acetylated lysine and decreases in pAKT and YAP. CUDC907 decreased tumor growth rate by 44% in a 14-day treatment regimen, modulated phospho-target levels, and decreased YAP levels. In five primary VS, CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials.